The United States continues to be a target of bioterrorism especially in the form of a radiological attack. This real possibility has prompted the need for countermeasures to protect against the biological effects of radiation poisoning. Historical data from radiation events in Japan and Chernobyl indicate that skin injury in conjunction with radiation exposure greatly increases both morbidity and mortality rates in individuals. The skin is vital in providing a barrier against harmful substances and protecting against pathogenic attack; two parameters that would certainly be compromised following a radiation-induced breach in this barrier. In the previous funding cycle, our group has made strides in deciphering key mechanisms responsible for acute and chronic effects of radiation in the skin, namely radiation-induced dendritic cell (DC) depletion and epidermal management of oxidative stress. This mechanistic data has lead to the discovery of potential agents that mitigate the above-mentioned effects of radiation. This proposal will further clarify the nature of the defects discovered in our initial studies to provide a foundation for multi-organ strategies for mitigating damage. These studies will greatly benefit from interactions with the other projects, particularly the bone marrow studies as effects on other organ system will undoubtedly affect immune functions in the skin. This proposal will explore how radiation alone or in combination with an additional skin injury will impair particular parameters essential to homeostatic function of the skin. In Aim 1, we will explore the mechanism and functional consequences of radiation-induced cutaneous DC depletion; a phenomenon we believe will leave the individual exposed to invading cutaneous pathogens. More importantly, we will address the impact of various agents in mitigating this loss. Aim 2 will test the hypothesis that radiation exposure impairs skin barrier function resulting from ROS-mediated damage and a hyperinflammatory response, which burdens the repair of secondary skin injury. Mitigating agents will be tested for their efficacy in restoring barrier function and reducing injury. Aim 3 will focus on the effects of radiation on special populations i.e. those of pediatric or adolescent age. In particular, we will examine whether radiation exposure at a young age results in a chronic barrier defect that impairs normal skin function later in life. The utility of mitigators found efficacious in Aims 1 and 2 will be tested in tills model.